Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
410=101=111MINIII.
A
CA 02642784 2008-08-28
Organic salts and method for producing chiral organic compounds
The present invention relates to a process for preparing chiral organic
compounds.
Many chemical transformations proceed via ionic intermediates and transition
states. Such
polar reactions are influenced by the particular counterion. For example, the
course of
reactions of carbanions can be modified by adding suitable cationic
substances. This
principle is well known in so-called phase transfer catalysis, in which the
reactions of
enolates and similar anionic substrates with various electrophiles can be
catalyzed
asymmetrically.
D. B. Llewellyn, B. A. Arndtsen describe, in Tetrahedron Asymmetry 2005, 16,
1789-1799,
reactions with reversed polarization, but no acceptable enantioselectivities
were realized.
It was accordingly an object of the present invention to provide a process for
preparing chiral
organic compounds, that to broaden the spectrum of chiral compounds with high
ee values,
preferably > 50%, preparable by synthesis, and also to enable the synthesis of
those
enantiomers which can be obtained only as enantiomer mixtures according to the
prior art.
The present invention accordingly provides a process for preparing chiral
organic
compounds by asymmetric catalysis using ionic catalysts, which is
characterized in that the
catalyst anion of the ionic catalyst is chiral.
It has been found that, surprisingly, it is possible by the process according
to the invention to
prepare chiral compounds in virtually enantiomerically pure form, in most
cases with an ee of
more than 90%, said compounds being obtainable only by complicated
purification methods
from the state. One example of this is the highly enantioselective reduction
of citral to the
perfume ingredient citronellal.
The process according to the invention is mediated by salt catalysts which are
composed of
a chiral or achiral cation and a chiral anion. In a preferred embodiment,
enantiomerically
enriched catalysts, i.e. catalysts which have an excess of one enantiomer, or
enantiomerically pure compounds are used. These catalysts can be prepared, for
example,
by reacting a chiral or achiral base with a chiral acid. Alternatively, the
catalytic salts can
. ,
CA 02642784 2008-08-28
_
- 2 -
also be prepared in situ from acid and base or by means of other common
methods known
to those skilled in the art. The chiral or achiral cation is preferably an
ammonium compound.
Typical examples of inventive catalysts are shown in scheme 1.
. ;.. '
fc ft f:
x"
x- rN>> x- R. .A. ,R
'
. NI N ¨
H2
H H
Ammonium salts R R
(primary and Imidazol(in)ium salts
Triazolium salts Amidinium salts
secondary amines
and ammonia)
R NI R2 . . = .
R I R.NI...R
1 4,
N Y
X¨ RNI-.. - Ai ¨
õN.R 0 (5 ¨
¨ =
H
H H
Ammonium salts N 4 X¨
x
i R
of tertiary amines H
Thiazol(in)ium salts
Guanidiniunn salts= =
Pyridinium salts
R R
. I+
RAl X¨
n X¨ R .13¨
I e. R I,.R
X
= . R ' M." X¨ H2N
y, NH2 R
Quatemary H
Quaternary =
ammonium salts Metal salts Pyridinium salts phosphonium
salts
. = .
=
= X¨ = chiral anion
=
Scheme 1. Selection of possible catalysts for processes according to the
invention.
The possible catalytic salts catalyze reactions which proceed via cationic
intermediates.
Such intermediates may, for example, be: iminium ions, N-acyliminium ions,
acylammonium
ions, phosphonium ions, sulfonium ions, oxonium ions or carbenium ions.
The process according to the invention suitable for preparing a multitude of
chiral
compounds is not limited to any specific reaction type. An important class of
possible
reactions is that of nucleophilic additions and cycloadditions of (a,13-
unsaturated) carbonyl
compounds which proceed via cationic iminium ion precursors, and are catalyzed
by salts of
primary and secondary amines (scheme 2). These include Diels-Alder reactions,
1,3-dipolar
cycloadditions, conjugated additions, epoxidations, cyclopropanations,
transfer
hydrogenations, Mukayama-Michael additions and Knoevenagel reactions. However,
the
principle is not restricted to these reactions.
= .
CA 02642784 2008-08-28
- 3 -
Such reactions have already been catalyzed asymmetrically. However, the
catalyst used
was always a salt which is composed of a chiral amine (as a base) and an
(a)chiral acid (or
the chiral amine alone). This invention, in contrast, provides for the use of
salts of achiral (or
chiral) amines with chiral acids.
4
R s,R
N x--
2 x- c"--, elecirophile
H -,-..\ X II chiral
lateamrs i,...===.. I 1 \ ' R L--
chiral or achiral
R
IL dienophile
IR' H20 ,.µ 11 acidic
.1
elecirophile
R,,, CHO +
0 --o. 1 R /41-10 Diels-Alder
reactions
arida cHo exo R
\
+ HQ
14¨ N-0
4iii to.y.õõ
1,3-dipolar cycloaddition
G . Cl CHO
, .
Ma MeN 1
.
_ 1+11
.................. lk R CIO conjugated addons
Fe-t......,...õ.. CHO + H202 ¨0.
n....õ77,....,..cHO epoxidations
. = = .
I a
4.
.11
R'...--%,..õ=. CHO .....S =¨ 0=.- '1.
cyclopropanations
Ph 41>tiCHO =
- R
H li
Me02C ' CO2Me i
R...k..,... CHO 4. 1 } R.-7-,,ZE10 transfer
hydrogenations
I-Pr =
H
?TMS
+ ...........4. "
CHO Mukaiyama-
Michael
R "..."Ph
addition
RTCHO 4. ?020
¨4. R,.y,A1
,...õ..õõGO2Et
Knoevenagel reaction
'CO2Et i ICO2Et
=
Scheme 2. Selection of possible reactions which can be catalyzed
asymmetrically by the
process according to the invention and proceed via iminium ions.
Another class of inventive reactions is that of acyl transfer reactions which
proceed via
cationic, activated acyl compounds, for example acylpyridinium ions. In this
way, it is
possible, for example, to catalyze kinetic resolutions of secondary alcohols
(Scheme 3).
CA 02642784 2008-08-28
- 4
NR2
1+¨ HO
0
A+ )\-0 HO
0 R'
_______________________________ R N
Rd/IL + HY ___________
R'
NR2 R'
Scheme 3. Kinetic resolution via asymmetric acyl transfer reaction as a
process according
to the invention.
The inventive catalyst anion is a chiral organic or inorganic anion.
Typically, it is selected
from chiral organic phosphates, sulfonates, sulfates, carboxylates, imides,
sulfonylimides,
etc. The anion preferably derives from unsubstituted or substituted
binaphthol. Particularly
good results are obtained when the anion is selected from binaphthol
derivatives with the
following formulae:
4010
.pp
/ is SO3 is
CO2
so d -0- es/ SO;
CO2
SO2
010 O'SC53 is CO _
_
040 0\s03-
00 CO 00 SO2
in which
R is hydrogen, substituted or unsubstituted alkyl or substituted or
unsubstituted aryl.
The cationic counterion used for the chiral anion used in accordance with the
invention may
be any cation. The cation is preferably selected from alkali metal ions and
ammonium ions,
particular preference being given to ammonium ions.
The term "alkyl" used means a linear, branched or cyclic hydrocarbon radical
which has
typically from 1 to 30, preferably from 1 to 24 carbon atoms, and especially
from 1 to 6
carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-
butyl, octyl,
decyl, etc., but also cycloalkyl groups such as cyclopentyl, cyclohexyl, etc.
The hydrocarbon
= .
CA 02642784 2008-08-28
- 5 -
radicals have preferably from 1 to 18, especially from 1 to 12 carbon atoms.
The aryl groups used in the context of the present invention are aromatic ring
systems
having 5 to 30 carbon atoms and optionally heteroatoms such as N, 0, S, P, Si,
in the ring,
where the rings may be simple or multiple ring systems, for example fused ring
systems or
rings bonded to one another via single bonds or multiple bonds. Examples of
aromatic rings
are phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone
and the like.
Substituted aryl groups have one or more substituents. Examples of heteroalkyl
groups are
alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated aminoalkyl and the
like. Examples of
heteroaryl substituents are pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl,
indolyl, pyrimidinyl,
imidazolyl, 1,2,4-triazolyl, tetrazolyl, and the like. Examples of heteroatom-
containing
alicyclic groups include pyrrolidino, morpholino, piperazino, piperidino, etc.
Possible substituents that the aforementioned groups may have include OH, F,
Cl, Br, I, CN,
NO2, NO, SO2, SO, amino, -COOH, -COO(C1-C6-alkyl), mono- and di-(C1-C24-alkyl)-
substituted amino, mono- and di-(C6-C20raryl)-substituted amino, imino, which
may in turn be
substituted, for example C1-C6-alkyl, aryl, and phenyl. Especially the cyclic
radicals may also
have C1-C6-alkyl groups as substituents.
Particularly suitable anions have been found to be those which derive from
binaphthol (e.g.
phosphates, sulfonates, sulfates, carboxylates, imides, sulfonylimides, see
Scheme 4).
However, the anions are in no way restricted to these structures.
OS R
0. p 4010 R
_ R _
SO3 is CO2
14
X- 00 d ''')--
00 so; 00 co2
R R R
is O'
R is R
00 R
SO2
SC-13 CO
\ _ \ _
N N
/
0401 (3\S03-
C OS /
O 010 802
R R R
Scheme 4. Selection of possible inventive anions.
CA 02642784 2008-08-28
- 6
The reaction conditions which exist for performance of the process according
to the
invention depend essentially on the reaction type selected and can be
established
immediately by the person skilled in the art.
Examples
Primary and secondary amine salts of chiral phosphoric acids highly
enantioselectively
catalyze the transfer hydrogenation of alpha,beta-unsaturated carbonyl
compounds with the
aid of Hantzsch esters (Scheme 5).
HH 0 y (HX) Li 0
R2)),, R3 R3
R7.)LR8
Rc)( -N, R2
R
8 RsRi o
R1 N R4 R5 R6 R1 N4 R5R6
Scheme 5. Transfer hydrogenation as an example.
For instance, the salt 1, in the presence of the Hantzsch ester 4, catalyzes
the highly
enantioselective transfer hydrogenation of various alpha,beta-unsaturated
aldehydes (2)
(Scheme 6). Further catalytic salts for the enantioselective transfer
hydrogenation are shown
in Schemes 7-9.
H 1-{
Me02CO21,Ae
1-Pr
CHO 4(1.1 eq) xCHO
Ar
la (20 mol%), dioxane Ar
50 C, 24h
2 3
PPr
Ar Yield 00
= (a) 4-MeC6H4 87% 96%
10110 t1-Pr0 0 (b) 4-NCC6H4 84% 97%
=0,p. (0) 4-NO2C6H4 90% 98%
000) 0- L112} (d) 4-131-C6H4 67% 96%
= 0
(a) 4-nFChoy1 k 99
C6114 7632:/o 98%%
1-13r m 2..asp
la
f-Pr
= = /-Pr
Scheme 6. Inventive highly enantioselective transfer hydrogenations.
...........,
CA 02642784 2008-08-28
- 7 -
7 .
I
I cat. (10 moi%), 4 (1.1 BM
__________________________________________________ 7.- H
40 1,4-dioxane 50 r'C, 24 h
ON 02N
. .
040 Ar
0.c,,0 e CO .
. .
cat.:
cr%
=
Ar: " . I. t 1 =
t t
. . 1. 1110 cy * *1
= lb to .1d le
cY
. 59 % conversion . 61 %conversion 51 % conversion 45
% conversion
95 % ee 88%ee = 93%ee . 82 % se
:=. I
1 1
1040 0100
isto .
lf 19 1110 1h
. ' 77 % conversion 71 % conversion 69 % conversion
96%ee = 96 % ee 95%ee
Scheme 7. Highly enantioselective transfer hydrogenation. Further examples of
morpholine
5 salts.
. .
CA 02642784 2008-08-28
- 8 -
_
=
t 0
=1 H cat. (10
mol%), 4 (1.1 eq.) = H
______________________________________________________ 1.
Si 111 1 oxane ,,4-di 50 6 C, 24 h .-
0
02N 02N ,
I-Pr si I-Pr .
'
=
=
O. I-Pr tz2
_
0, =
i e 102
= cat.: _R,0 1.
D....w... .
. 0¨ \` =
040 1-43r 112
0 .
/-Pr I-Pr =
=
= Me0 .
Mtn .
111.0-Ft
# ill = r-S N =
112 ' =
= =
' if L)e
BriAan
H3rte ern43 13 K2 ik H2 11 .H
.
37 %conversion 49 % conversion = 100 %
conversion 90 % conversion =
96 % ee 97%ee 97 % ee 95 % ee
H
=
H
ceNNio. .
O A
co2Et
H2 N N N H
=
H2 H2 K2
82 % conversion 28 % conversion 22 % conversion 28 %
conversion 78 % conversion
= 97%ee 97 % ee 97 % ee 95 % ee 95 %
ee
Scheme 8. Highly enantioselective transfer hydrogenation. Further examples of
various
3,3'-bis(2,4,6-triisopropylpheny1)-1,1'-binaphthy1-2,2'-diy1 hydrogenphosphate
salts.
. =
CA 02642784 2008-08-28
_
- 9 -
,
0
0
1 H cat. CIO rnot%), 4 (1.1 et:14- H
11
,.,, 1 1, 4-dioxane , 50 T, 24 h
= Li 01
21.4"10 02N
= .
140 4
cat.: 0. 0101
.
2 0, me Ph>41h
0õoe H2
=
4* 0 H3N "
e eNH3 - 0. la
' * 87' % conversion
= 91 % ea ,w,
= 4% conversion
05%ee =
1 r Is =
.
. . . =
1-P . 1-Pr . illiai&I
0 F
0õ00 Ca) o õoet
-% -1:
. el. .
o N
H2
1-Pr o N2 W
4040
33 % conversion
= 1-Pr 93% ee
O. 69 % conversion
11 . 97 %
ee
lu
. * .
. .
OS 400 .
= =
oõoe H2 .
Aci . BrftBn .
=
APO 71 % conversion .
liP 1v " % " .
_ =
Scheme 9. Highly enantioselective transfer hydrogenation. Further examples.
This reaction can be extended to the industrially important substance citral,
which is reduced
highly enantioselectively to the perfume ingredient citronellal (Scheme 10).
CA 02642784 2008-08-28
- 10 -
_
HO HO
ii 4 (1 . eq)
la (20 mol%)
THF, 20 C, 24h
71%
=
citral (6) (F)- citronella! (6)
91% as
Scheme 10. Inventive highly enantioselective transfer hydrogenation of citral
EtOP
N
1 w (10 mal%), 5 (I.1 eq.)
THF, Lt., 66 h
73 % conversion
i-Pr 14Pr 91 % e e
=
0õ0 Si*
.13:& NH3
040 b
11110 lw
=
I-Pr I-Pr
Scheme 11. Inventive highly enantioselective transfer hydrogenation of an
aliphatic
substrate
Experimental section
Preparation of the salts
The acid (1 eq) in diethyl ether (2m1/mmol) was initially charged and the
particular amine
(1 eq) was added in one portion. After stirring at room temperature for from 2
to 15 hours,
the salt formed was filtered off or the solvent was evaporated off on a rotary
evaporator. The
salts were obtained in quantitative yields.
CA 02642784 2008-08-28
-11 -
Asymmetric transfer hydrogenation
The aldehyde (2a-f) (1 eq) and catalyst (1a-1w)) (0.2 eq for la, or 0.1 eq for
lb-1w) were
initially charged in THF (aliphatic substrates) or 1,4-dioxane (aromatic
substrates)
(10 ml/mmol), and the mixture was stirred at room temperature (aliphatic
substrates) or 50 C
(aromatic substrates) for 2-5 min. Thereafter, Hantzsch ester (4 or 5) was
added and the
mixture was stirred for a further 24 hours. The reaction mixture was
supplemented with
water (40 ml/mmol) and extracted with diethyl ether (aliphatic substrates) or
methylene
chloride (aromatic substrates) (3 x 40 ml/mmol). The combined organic phases
were dried
over magnesium sulfate and concentrated on a rotary evaporator.
Column chromatography (pentane/diethyl ether or hexane/ethyl acetate) gave the
products
in the yields and enantiomeric excesses reported.
For the examples shown in Schemes 7-9 and 11, a sample was taken and the
conversion
was determined by means of NMR.
Asymmetric transfer hydrogenation of a,P-unsaturated ketones (new chapter)
The process can also be applied to a,13-unsaturated ketones. Especially chiral
phosphate
salts of primary amino acid esters have been found to be high performance and
highly
enantioselective catalysts.
For instance, the salt 7a, in the presence of the Hantzsch ester 8, catalyzes
the highly
enantioselective transfer hydrogenation of various a,13-unsaturated ketones
(9) (Scheme 12).
Further catalytic salts for the enantioselective transfer hydrogenation are
shown in Schemes
13-15.
. '
CA 02642784 2008-08-28
_
- 12 -
H 11
Et02 I ' 1CO2Et
=
.
N
0 . H
Riii 8 (1.2 eq) ,. R1'31. =
1 ,
R2 R3 Ta (5-10 mol%), 81.120 R2 R3
=
60 C, 48 h
9 10
= -
=
I-Pr RI R2 R3 Yield ee
i-Pr 410, (a) ¨(CH2)2-- Me 78% 98%
(b) ¨(CH2)2.-- Et
71% 97%
100PrP
(c) --(CH2)2.¨ CH2CH2Ph ea% 96%
0:-o +
(d) ---(CH03¨ Me 99% 94%
.
, HaN CO2t-Bu
(e) _(CH¨ Et
P... '`.., 98% 96%
/ Cr (f) ¨(CH-- PEW
89% 95%
101410 0 i.451. 14:=,.1. (9) CF12)3--- 1-Pr
94% . 98%
(b) ¨(CH¨ CH2CH2Ph 99% 96%
(i) -(CH--- ph
99% 84%
1*7a 0OH-- me
>99% 97%
API- - (k) Me Me CO2Et >99% 83%
,
= i-Pr (0 Me
Me Ph 81% 69%
. _________________________________________________________________________ ,
. ..= . .
Scheme 12. Inventive highly enantioselective transfer hydrogenations.
CA 02642784 2008-08-28
- 13-
0
cat. (20 mol%), 8 (1.2 eq) =
=
Etz0, 40 6C, 44 h
=
,,R =
0. ,0 H3N.,CO2t-Bu
cat.:
O. 1-Pr
= =
110
7b lo 7d le
9 % conversion 9 % conversion 18 % conversion 75 %
conversion
74 % ee 88 % ee 85 % ee =96 % ee
s. isos 4* 0
'Tf 7g
% conversion 10 % conversion 7 % conversion
rr % ee 44 %ee 77 ')/0 ee
=
Scheme 13. Highly enantioselective transfer hydrogenation. Further examples of
tert-butyl
valinate salts.
5
. .
CA 02642784 2008-08-28
- 14 -
_
= .
=
=
cat. (20 mol%), 8(1.2 eq) .
6...
1,4-dioxane , 60 C, 48 h
I-Pr 40 I-Pr
=
. 0õ0 32 =
cat.: P
00 HNR
O. ' -
, J.-Pr1:1 Ri
..
= .
. .
= IS =
i=Pr
= =
. +
+H2N.,,,...0O2Me
= =
H3N,CO2t-Bu . H3N.õ..0O2Me .
z.
+1-r3r
= . H3N./11`. T1
n = 7k
23 %
11-1 2 = 66 %conversion 14 %conversion
conversion
84 % ee
,
47 % ee 61 % ee
. '
+ + ., + +
H3N ,,O02Me HaNN,CO2Me H3N CO2Ma .
H3NC04t-Bu
. ..
.:.
t-tio ' 15h lEih Me
= 71 7m 7n
To
12 % conversion 10 % conversion 17 % conversion
27 % conversion
= 76 % ee 59 % ee 76 %
ee 82 % se
=
=
=
+ 4' +
. - H3N-,,,,,-0O2t-Bu H314-,CO2t-Bu
H3N,,..,CONMe2 =
=
. =
. i-Pr = tu . t-
Bu .
= 7p 7q Tr
14% conversion 18% conversion
10 % conversion
91 % ee 90 % ee 62 % ee
.
Scheme 14. Highly enantioselective transfer hydrogenation. Further examples of
various
3,3'-bis(2,4,6-triisopropylpheny1)-1,1'-binaphthy1-2,2'-diy1 hydrogenphosphate
salts.
CA 02642784 2008-08-28
- 15 -
= 0
= cat. (26 mcl%), 8(1.2 eq)
= 1,4-dioxane, 60 C, 46 h
f-Pr si I-Pr
0401. I-Pr _ 4.
cat.:
H3N,..õ,.0O2t-Bu
0., .
\
=00, 1-.15r
1-Pr I-Pr
V.
I* f-Pr -I-Pr [-Pr
=
/-Pr =411111.1 i-Pr
-P
= 0 0
4114111 i-Pr 0001
. = =
f-Pr I-Pr f-Pr i-Pr
= , 7p Is
81 % conversion 48 %conversion
16 % ee
94 %.ee
Scheme 15. Highly enantioselective transfer hydrogenation. Examples of the
"matched/mismatched" effect.
Experimental section
Preparation of the salts
The acid (1 eq) in diethyl ether (2 mVmmol) was initially charged and the
particular primary
amine (1 eq) was added in one portion. After stirring at room temperature for
from 2 to 15
hours, the salt formed was filtered off or the solvent was evaporated off on a
rotary
evaporator. The salts were obtained in quantitative yields.
CA 02642784 2008-08-28
- 16 -
= Asymmetric transfer hydrogenation
The ketone (9a-I) (1 eq) and catalyst (7a-s) (0.1 eq for 9a-c, or 0.05 eq for
9d-I) were
initially charged in Bu20 (0.33 ml/mmol), and the mixture was stirred at 60 C
for 2-5 min.
Thereafter, Hantzsch ester (8) (1.2 eq) was added and the mixture was stirred
for a further
48 hours. The reaction mixture was supplemented with sodium hydroxide solution
(2N,
40 ml/mmol) and extracted with diethyl ether (3 x 40 mVmmol). The combined
organic
phases were dried over magnesium sulfate and concentrated on a rotary
evaporator.
Column chromatography (pentane/diethyl ether) gave the products in the yields
and
enantiomeric excesses reported.
For the volatile saturated ketones, and also for the examples shown in Schemes
13-15, a
sample was taken and the conversion was determined by means of GC.
Asymmetric epoxidation
It is also possible to catalyze epoxidations in a manner analogous to Scheme
2. For
example, cinnamaldehyde can be converted using tert-butyl hydroperoxide
enantioselectively to the corresponding epoxide when the catalysts used are
the salts llbw
(Scheme 16).
CA 02642784 2008-08-28
-17-
. 0
libw (JO mcil%) 0
TBHP _____________________________________________
R H dioxane, 72h R
(1.1 eq)
12 13
f-Pr
- 40116 0
cat.: P( f-Pr
F30 110 H2
140 CF3
=000 ci
f-Pr CF3 CF3=
=
=
1-Pr
Yield dr ee
(a) Ph ' = 75% >99 : 1 91%
== (b) 2-naphthy1 76% >99 : 1 95% ,
= (c) 1-naphthyl 70% 98 :2 91% '
= (d) 4-Ph-C6H4 78% >99 : 1 91%
= (e) 4-Me-C6H4 65% >99: 1 92%
(f) 3-Me-C61-14. 68% >99 : 1 92% '
(9) 2-Me-C8H4 62% 97 : 3 90%
(h) 4-cyc1ohexyl-C$H4 60% >99 : 1 90%
(i) 4-F-06H4 78% >99 :
1 93%
3-F-C6H4 82% >99 1 84%
(k) 2-F-C6H4 69% 98 : 2 91%
= (1) 4-01-C3 H4 84% >99: 1 87%
= (m) 4-Br-C6H4 BO% >99 : 1
87% =
= (n) n-hexyl 92% 95 : 5 70%
Scheme 16. Inventive highly enantioselective epoxidation
. ,
CA 02642784 2008-08-28
,
- 18 -
0 cat. (10 mot%) 0
phs',""kõ:"Jj'== 1.1 + TBHP
dioxane, 55 C
0.5 eica
.
-
O. i-Pr
cat.: )20". R-A-RI
. 0 112
R..ki..R1 PP *
14 i-Pr
'
õ...11,-õ,
*t4H2 Ph NH2
... .../ H X ( mesa-
)
Ph NH2
ilea *Ptah liac had liae
. .
14% yield 49% yield 61% yield = 35% yield 19% yield
. 98:2 dr,11% ee 71 : 29 dr, 7% ee 95 1 5 dr, 4% ee 84 : 2.0 dr, -8% ee .
97 :37 dr, 2% ee .,
. ryNVI2 .
Ph
.
9
1Iaf flag 11ah Ilal
Ilaj
13.5% yield 59% yield 57% yield 55% yield
51.3% Yield
70 : 30 dr, -15% es . 89 : 1 1 dr, 47% se 80 : 20 dr, 64% se 95 : 5 dr, 54% ee
91 : 9 dr, 46% ee
=
1.)
r........N1 ts1 0
Or
H H n H N
H
11 ak Ilal 11am 11an 11ao
hap
22% yield 29.7% yield 59% yield 25% yield
25% yield 15% yield
93 : 7dr, 40% ee 93 : 7dr, 55% es 96 :4 dr, 72% ee 94:6dr, 66%ee 93:7dr, 67%
ee 93 : 7 dr, 8% ee .
110 411] m>
IP H ioi
"'N. I re
Si
i 4110= Pi 1* H
Onesp4 I
llaq liar has hat lieu
.
40% yield 67% . yield 33% yield 45% yield
79% yield
95:5 dr, 71% ee 94:6 di, 40%ee 95:5 dr, 44% ee 8515 dr, 50% ee 95:5 di, 70%
ea . .
CA 02642784 2008-08-28
- 19 -
-
liav liaw ilax
95% yield 49% yield 57% yield
982 dr, 66% ea = 93:7 dr, 55% ee 97:3 dr, 77%
ea =
r'N.N.='\)%."Nhr\.. Me02C'1"."`CO2Me Ef02e11"`co2Et
hay ilaz liba
.54% yield 52% yield 70% yield
88 :12 dr, 8% ee 82 :18 dr, 55% ee 95:5dr, 76%ee
ButO2C".NCO2But
=
= 11bb llbc
38% yield = 18% yield 54% yield
92:8 dr, 57% ee 91: 9 dr, 610/0 ea 94 : 6 dr,
60% eie
Scheme 17. Highly enantioselective epoxidation. Further examples of various
3,3'-bis(2,4,6-
triisopropylpheny1)-1,1'-binaphthy1-2,2'-diy1hydrogenphosphate salts with
commercial achiral
amines.
CA 02642784 2008-08-28
- 20 -
0 cat. (.10 mono 0
,e9 it
Ph`,...-...).H + TBHP ____________________________ 0
Pll'¨`1H .
dioxane, 55 ad
(t5 eq)
i-Pr
=
. i-P illt . .
=
= 110 I-Pr
= cat.: . q,
,0
11R` =
. **, .4.11-2
P - ..
.
'00 d o
A-Pr
' = ,
. .
.. I-Pr *
' . =
i-Pr =
=
. . . .
= .
Ph'
. Ph . Ph-(
)"ph ti. Ph`'
.-"Ph .
µ'Nr-A,`"' Ph- aNt\
' (RA).- .. cis- (S,S)- ti
(S)- H .
111;0 11 tit ilbg libh
=
=
40% . yield = 85% yield >95% Yield 21:6% yield
76:24 dr,4%ee. 98:2dr.56%ee >99:1dr,82%ee 89
:11dr,42%ee
. ,Ph _
=
:
..Ø,
,t, 410 IA i 0
(S)- H . ph (s)..Y 1C (s,$).-N (S,S)-
0
ilbt lib] 111* 11131
81% yield 55% yield 53% yield 27% yield
96 : 4 dr, 87% ee 95 : 5 dr, 79% ee 89 :11 dr, 15% Ge 90 : 10 dr, 2
9 % ee
Scheme 18. Highly enantioselective epoxidation. Further examples of various
3,3'-bis(2,416-
5
triisopropylpheny1)-1,1'-binaphthy1-2,2'-diy1hydrogenphosphate salts with
chiral amines
CA 02642784 2008-08-28
- 21
0
TBHP cat. (10 mai%)
Ph
phr- "1"' `H =
(1.5 )
dioxane, 55 C
eq
I-Pr
cat.: 11101. O
=
=
040 0 ppr
I-Pr *
1-Pr
. ,
RR=
=
0 14 0
ly = 401 -
N%".=
llbm 11bn llba
22% yield 35% yield 58% *10. _
71:29 dr, 26% ee 94:6 dr, 22% ea
93:7 dr, 73% ee
Scheme 19. Highly enantioselective epoxidation. Further examples of various
3,3'-bis(2,4,6-
triisopropylpheny1)-1,1'-binaphthy1-2,2'-diy1 hydrogenphosphate salts with
benzoic
hydrazides
_
. .
CA 02642784 2008-08-28
-
-22 -
,
. .
cat. (10 rnol%) _<=:f_i
+ r
= '
1BHP ___________________________________________________ = Ph H
dioxane , 55 C
. ' 0.5 eq)
' - r =
=
=
. PPr 411
- =
cat.: IPSO 0 Wo r '
. ..,,,
= 0140 d o
Ha
- .
. - = = F = F
' F3 CF2 F F =
010 Pi *0 .110
10 F 10 N *
F F
.
F
=
P F
libp ' ' 'Mg llbr . = -
87% yield = 52% yield 25% yield - =
95:5 dr, 59% ee 96:4 dr, 59% ee 96:4 dr, 73% ee
=
. Si 10 . ilk . 1 10 Ililiii,,.
IP N 0 c3
,
0 vi 10 .
cF3
= fibs if bt
11bu
94% yield 75% yield 55% yield
-
973 dr, 66% ea 94:6 dr, 55% ee 98:2 dr, 83%
ee =
-
io
F3 101 4 is c3 io N 110 cF,
6 N 16 .
02N NO2
F3
=
11bv . 11bw 11bx
= =
= 67% yield 71% yield 53% yield
=
97:3 dr, 78% ee >99:1 dr, 90% ee =
98:2 dr, 64% ee
=
Scheme 20. Highly enantioselective epoxidation. Further example of various
3,3'-bis(2,4,6-
triisopropylpheny1)-1,1'-binaphthy1-2,2'-diy1 hydrogenphosphate salts with
dibenzylamines
CA 02642784 2008-08-28
-23-
9
Ph H cat. (10 mol%)
Tpt.lp
_ey
dioxane , 55 C PI(
AH
(1.5 eq)
= cat.: 0111* 0õ.
N2 =
00*
=
R:
. .
it, .44 NO2
.1495"'
1 lbx . llby ilbz lice
75% yield 67% yield 70% yield 54% yield
98:2 dr, 25% ee 98:2 dr, 21% se 98:2 dr, 31% se 96:4 dr, 15%
ee
=
CF3
=411 - *O.
cF3
cb lice lied lice
48% yield 62% yield 55% yield 75% yield
98:2 dr, 12% se = 93:7 dr, 24% ee 98:2 dr, 22% ee 98:2 dr, 25% ee
=
411 0140 CO2H CF3
1
R=- * 0110 040 Ø2H
c,3
=
= itch
95% yield 95% yield 70% yield
- 982 dr, 38% se 982 dr, 66% ee 9713 dr, 4% es
Scheme 21. Highly enantioselective epoxidation. Further examples of various
dibenzylamine salts
CA 02642784 2008-08-28
- 24 -
0 cat. (10 mot%)0
. _ect =
ph + TBHP ______________________ Pfr
(1.5 eq) dioxane , 55 C
10110 .,0 a
7N = "3
440 H,
R CF3 CF3
R: =
000 100
= =
= lid! =llcJ llbw =
45% yield 81% yield 71% yield
>99:1 di; 54% es 99:1 dr, 62% ee >99:1 dr, 90% ee
Scheme 22. Highly enantioselective epoxidation. Further examples of various
bis(3,5-bis(tri-
fluoromethyl)benzyl)amine salts
CA 02642784 2013-08-07
-25 -
= .
,,.e...... CHO = =
= *.
. L-CHO
Ilbw (10 mai%)
+ TBHP ___________________________________________________ =-=
1 (1.1 aq) . solvent , rt, 24 h
I
..
14 (Z/E=1:1) . . 15
. =
i-Pr Alp =
. - .
. .
1100 /--Pr
. .
F30 0 N
H is C,3
,
= P,
0 .
Cfs eh
.. .
. 1.-P 410 ' . .
.
. . .
. .
. I-Pr
_
= . . 11but .
.
= .
- Solvent Conversion - dr ea
.
(a) dioxane 95% 73:27 . ea% /89%
= (b) MIME 95% 72:28
76% /91% .
(c) Bu20 95% 78:22 81% /86%
(d) Et20 95% 7525 78% / 90%
..
Scheme 23: Inventive highly enantioselective epoxidation of citral
Experimental method:
Cinnamaldehyde (1 mmol) in dioxane (4 ml) is admixed with the catalyst (0.1
mmol,
mol%) and t-BuO0H (1.1 mmol, 1.1 eq), and the reaction mixture is stirred at
35 C for
10 3
d. The reaction mixture was supplemented with a 10% NaHS03 solution (4 ml) and
extracted with diethyl ether (3 x 4 m1). The combined organic phases were
dried over
magnesium sulfate and concentrated on a rotary evaporator.
Column chromatography affords the pure epoxide in the yields and ee's
reported.
CA 02642784 2013-08-07
- 26 -
Asymmetric acyl transfer reaction
In accordance with Scheme 3, the novel catalysis strategy with chiral anions
can also be
extended to acyl transfer reactions. Reaction of a-phenylethanol with acetic
anhydride in the
presence of salts 16 and 17 takes place with clearly measurable
enantioselectivity
(Scheme 24).
OH OH OAo
16 otil (10 moi
Ac20 ____________________________________________
110 *
0.5 eq toluene, 24h 1
=
=
11040 =
*SI 10,0 NI
- sr
-0
I + 00
. 0,P-0
= 11
.
110
. = .
16 17 11101
45% conversion, 8.4/13.5% ee (alcohoVester)
39% conversion, 10.4/22.6% ee (alcohoVester)
Scheme 24. Inventive enantioselective esterification
Experimental method:
The use of salt 16 is illustrative. For instance, the chiral phosphoric acid
(TRIP, 7.53 mg,
0.01 mmol) and DMAP (1.22 mg, 0.01 mmol) in toluene (1 ml) is stirred for one
hour.
Subsequently, the racemic alcohol (0.1 mmol) and Ac20 (0.05 mmol, 0.5 eq) are
added.
After the conversion reported, the product is isolated via aqueous workup.
